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| Open AccessComprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2
Lynch syndrome is characterized by predisposition to colorectal cancer and mutations in genes involved in mismatch repair. Here, the authors use whole genome sequencing and immunohistochemistry of mismatch repair proteins to show a high prevalence of Lynch syndrome in the Icelandic population.
- Sigurdis Haraldsdottir
- , Thorunn Rafnar
- & Kari Stefansson
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Article
| Open AccessKDM3 epigenetically controls tumorigenic potentials of human colorectal cancer stem cells through Wnt/β-catenin signalling
Epigenetic factors can regulate functional properties of human colorectal cancer stem cells. Here, the authors show that histone demethylases of the KDM3 family activate Wnt signalling in colorectal cancer stem cells by erasing H3K9me2 marks on Wnt target genes and recruiting MLL1 to promote H3K4 methylation.
- Jiong Li
- , Bo Yu
- & Cun-Yu Wang
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Article
| Open AccessPhylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations
Tumour heterogeneity is well-known; however, studies analysing the progression from primary to metastatic disease are still limited. Here, the authors used phylogenetic analyses and found that for some patients there are multiple seeding events from the primary tumour accompanied by cross-seeding between metastases.
- David Brown
- , Dominiek Smeets
- & Christine Desmedt
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Article
| Open AccessClonal evolution in myelodysplastic syndromes
Myelodysplastic syndromes are a broad group of haematopoietic malignancies that often progress to acute myeloid leukaemia. Here, the authors show that linear and branched evolution occurs within myelodysplastic syndrome and these patterns can be impacted by treatment.
- Pedro da Silva-Coelho
- , Leonie I. Kroeze
- & Joop H. Jansen
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Article
| Open AccessInhibiting the system xC−/glutathione axis selectively targets cancers with mutant-p53 accumulation
Efficient therapeutic strategies to target mutant-p53 cancers are needed. Here, the authors demonstrate the molecular mechanism through which mutant-p53 tumours are susceptible to oxidative damage and propose a potential strategy for targeting such cancers by inhibiting the SLC7A11-glutathione axis.
- David S. Liu
- , Cuong P. Duong
- & Nicholas J. Clemons
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Article
| Open AccessProteogenomic integration reveals therapeutic targets in breast cancer xenografts
Patient-derived xenografts recapitulate major genomic signatures and transcriptome profiles of their original tumours. Here, the authors, performing proteomic and phosphoproteomic analyses of 24 breast cancer PDX models, demonstrate that druggable candidates can be identified based on a comprehensive proteogenomic profiling.
- Kuan-lin Huang
- , Shunqiang Li
- & Li Ding
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Article
| Open AccessRational combination of oncolytic vaccinia virus and PD-L1 blockade works synergistically to enhance therapeutic efficacy
Anti-PD-L1 therapy often fails in cancers with minimal lymphocytic infiltrates and low PD-L1 expression. Here, the authors show that an oncolytic virus increases PD-L1 expression in cancer models and that the combination with an anti-PD-L1 antibody enhances therapy by increasing the infiltration of activated T cells, and reducing exhausted T cells.
- Zuqiang Liu
- , Roshni Ravindranathan
- & David L. Bartlett
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Article
| Open AccessThe scaffold protein p140Cap limits ERBB2-mediated breast cancer progression interfering with Rac GTPase-controlled circuitries
p140Cap adaptor proteins interfere with adhesion and growth factor-dependent signalling in cancer cells but the mechanisms are unclear. Here the authors show that p140Cap interferes with ERBB2-dependent activation of Rac GTPase-controlled circuitries reducing metastasis and cancer progression.
- Silvia Grasso
- , Jennifer Chapelle
- & Paola Defilippi
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Article
| Open AccessSuppressive IL-17A+Foxp3+ and ex-Th17 IL-17AnegFoxp3+ Treg cells are a source of tumour-associated Treg cells
Th17 cells can transdifferentiate into regulatory T (Treg) cells. Here the authors characterize tumour-driven Th17-to-Tregcell transdifferentiation and identify potential cancer therapy targets.
- Stephanie Downs-Canner
- , Sara Berkey
- & Nataša Obermajer
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Article
| Open AccessMAX inactivation is an early event in GIST development that regulates p16 and cell proliferation
In gastrointestinal stromal tumours early mutations in known genes are frequently followed by chromosome 14q deletion. Here the authors find mutations resulting in loss of MAX protein expression conserved between primary tumours and metastases in the same patients, suggesting thatMAXmutation is an early event.
- Inga-Marie Schaefer
- , Yuexiang Wang
- & Jonathan A. Fletcher
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Article
| Open AccessSpatiotemporally restricted arenavirus replication induces immune surveillance and type I interferon-dependent tumour regression
Viruses are promising anti-tumour therapeutics due to induction of an immune response and/or oncolytic activity. Here, Kalkavanet al. show that LCMV replicates in tumour cells, without inducing cell lysis, and that its anti-tumour activity is largely mediated by recruitment of interferon-producing monocytes.
- Halime Kalkavan
- , Piyush Sharma
- & Karl S. Lang
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Article
| Open AccessAn integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer
KRAS-driven cancers remain refractory to current clinical therapies. In this study, the authors show that lung and pancreatic cancers expressing oncogenic KRAS can be targeted by genetic inhibition of FOSL1, which involves downregulation of genes of the mitotic machinery.
- Adrian Vallejo
- , Naiara Perurena
- & Silve Vicent
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Article
| Open AccessCX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours
Stabilization of DNA quadruplex structures (G4) is lethal for cells with a compromised DNA repair pathway. Here, the authors show that CX-5461, a small molecule in clinical trials as RNA polymerase inhibitor, has G4-stablization properties and can be repurposed to target DNA repair-defective cancers cells.
- Hong Xu
- , Marco Di Antonio
- & Samuel Aparicio
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| Open AccessTHZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors
T-cell lymphomas are aggressive diseases associated with poor outcome. Here, the authors show that the THZ1, a CDK7 inhibitor, suppresses STAT transcriptional activity leading to apoptosis and sensitization to BCL2 inhibitors in T-cell lymphomas.
- Florencia Cayrol
- , Pannee Praditsuktavorn
- & Leandro Cerchietti
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| Open AccessDNA copy number changes define spatial patterns of heterogeneity in colorectal cancer
The contribution of intra-tumour heterogeneity is increasingly associated with resistance to therapy. Here, the authors use genomic analyses to study heterogeneity in colorectal cancer and perform in-depth reconstruction of heterogeneity in one sample.
- Soulafa Mamlouk
- , Liam Harold Childs
- & Christine Sers
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Article
| Open AccessA human immunodeficiency syndrome caused by mutations in CARMIL2
CARMIL2 (Rltpr) is involved in T-cell function. Here, the authors identify human CARMIL2-deficiency as an autosomal recessive primary immunodeficiency disorder characterized by EBV+smooth muscle tumours, CD28 co-signalling deficiency and impaired cytoskeletal dynamics.
- T. Schober
- , T. Magg
- & F. Hauck
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Article
| Open AccessExome and genome sequencing of nasopharynx cancer identifies NF-κB pathway activating mutations
Nasopharyngeal cancer is frequently characterized by Epstein-Barr virus infection. Here, using genomic analyses, the authors find that the tumours harbour mutations in genes involved in the NF-κB signalling pathway or overexpress a viral oncoprotein, latent membrane protein 1.
- Yvonne Y Li
- , Grace T. Y. Chung
- & Kwok-Wai Lo
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Article
| Open AccessA signature motif in LIM proteins mediates binding to checkpoint proteins and increases tumour radiosensitivity
CDC25 phosphatases are important cell cycle regulators. Here, the authors show that the LIM domain-containing proteins (for example, FHL1) induce inhibitory CDC25 phosphorylation resulting in radioresistance and that a specific peptide can increase tumour radiosensitivity by increasing CDC25 activity.
- Xiaojie Xu
- , Zhongyi Fan
- & Qinong Ye
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Article
| Open AccessMutant U2AF1-expressing cells are sensitive to pharmacological modulation of the spliceosome
Spliceosome mutations occur in approximately 50% of patients with myelodysplastic syndromes. Here, the authors show that tumour cells harbouring theS34F mutation in the U2AFspliceosome gene is sensitive to compounds that further perturb the spliceosome.
- Cara Lunn Shirai
- , Brian S. White
- & Matthew J. Walter
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Article
| Open AccessGermline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories
Men that carrierBRCA2germline mutations are at risk of developing prostate cancer. Here, the authors analyse the genomes of prostate cancer from these individuals and demonstrate increased genomic instability in comparison to sporadic prostate cancer.
- Renea A. Taylor
- , Michael Fraser
- & Robert G. Bristow
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Article
| Open AccessHollow boron nitride nanospheres as boron reservoir for prostate cancer treatment
Use of soluble boron compounds in prostate cancer therapy is hampered by their short half-life time and low effectiveness. Here, the authors show that boron nitride nanospheres with controlled boron release can reduce proliferation of prostate cancer cells and inhibit tumour growth in animal models.
- Xia Li
- , Xiupeng Wang
- & Dmitri Golberg
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Article
| Open AccessCDK4/6 or MAPK blockade enhances efficacy of EGFR inhibition in oesophageal squamous cell carcinoma
Oesophageal squamous cell carcinoma often develop resistance to EGFR tyrosine kinase inhibitors. Here, the authors demonstrate that inhibition of cell cycle regulators CDK4/6 or MAPK blockade enhances the efficacy of EGFR inhibitors for these tumours in mice.
- Jin Zhou
- , Zhong Wu
- & Adam J. Bass
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Article
| Open AccessReprogramming the immunological microenvironment through radiation and targeting Axl
Radiotherapy can enhance the antitumour immune response. Here, the authors show that resistance to radiation in breast cancer cells can be due to Axl expression that suppresses antigen presentation though MHCI, promotes NF-κB signalling, and enhances cytokine release promoting a suppressive myeloid microenvironment.
- Todd A. Aguilera
- , Marjan Rafat
- & Amato J. Giaccia
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Article
| Open AccessGALNT14 promotes lung-specific breast cancer metastasis by modulating self-renewal and interaction with the lung microenvironment
Polypeptide N-acetyl-galactosaminyltransferases (GALNTs) are associated with cancer, but their function in organ-specific metastasis is unclear. Here the authors show that GALNT14 promotes breast cancer metastasis to the lung by enhancing the initiation of metastatic colonies and subsequent growth.
- Ki-Hoon Song
- , Mi So Park
- & Mi-Young Kim
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Article
| Open AccessAcquired RAS or EGFR mutations and duration of response to EGFR blockade in colorectal cancer
Some colorectal cancer patients respond well to treatment with anti-EGFR antibodies, however response is almost invariably followed by acquired resistance. Here, the authors show that patients with shorter responses acquireRAS mutations, while those relapsing later preferentially develop mutations in the extracellular domain of EGFR.
- Beth O. Van Emburgh
- , Sabrina Arena
- & Alberto Bardelli
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Article
| Open AccessIntegrin α7 is a functional cancer stem cell surface marker in oesophageal squamous cell carcinoma
There is still no consensus on tumour type-specific cancer stem cell markers. Here, the authors demonstrate that ITGA7 is a potential functional marker of oesophageal cancer stem cells involved in the resistance to chemotherapy and metastasis through activation of FAK-mediated signalling.
- Xiao-Yan Ming
- , Li Fu
- & Xin-Yuan Guan
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Article
| Open AccessTruncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer
Castration-resistant prostate cancer frequently presents with persistent androgen receptor signalling. Here, the authors find that the androgen receptor is subject to genetic rearrangements, resulting in variants with ligand-independent activity.
- Christine Henzler
- , Yingming Li
- & Scott M. Dehm
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Article
| Open AccessIRS4 induces mammary tumorigenesis and confers resistance to HER2-targeted therapy through constitutive PI3K/AKT-pathway hyperactivation
IRS proteins are scaffolds that can activate survival signalling pathways. In this study, the authors identified IRS4 as a potential oncogene in breast cancer that leads to the constitutive activation of PI3K/AKT signalling and thus confers resistance to HER2-targeted therapy.
- Gerjon J. Ikink
- , Mandy Boer
- & John Hilkens
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Article
| Open AccessLineage-specific roles of the cytoplasmic polyadenylation factor CPEB4 in the regulation of melanoma drivers
Cytoplasmic polyadenylated transcripts have been poorly characterized, particularly in cancer. Here the authors identify a lineage-specific requirement of the cytoplasmic polyadenylation binding protein 4 (CPEB4) in malignant melanoma and show that it controls melanoma drivers MITF and RAB27A.
- Eva Pérez-Guijarro
- , Panagiotis Karras
- & María S. Soengas
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Article
| Open AccessDendritic cell-elicited B-cell activation fosters immune privilege via IL-10 signals in hepatocellular carcinoma
Activation and biological function of B cells in cancer are still unclear. Here, the authors show that hepatocarcinoma cells drive the formation of semimature dendritic cells that in turn activate FcγRIIlow/−tumour B cells through the CD95L/CD95 axis, leading to the production of IL-10 and suppression of CD8 T cells.
- Fang-Zhu Ouyang
- , Rui-Qi Wu
- & Dong-Ming Kuang
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Article
| Open AccessTheranostic barcoded nanoparticles for personalized cancer medicine
Determining the most effective treatment for each cancer patient is a key challenge in cancer therapy. In this article, the authors show, in a mouse model of breast cancer, that DNA barcoded nanoparticles can be used for pre-screening the efficacy of anticancer drugs.
- Zvi Yaari
- , Dana da Silva
- & Avi Schroeder
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| Open AccessImpact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation
Aromatase inhibitors are used to treat oestrogen receptor positive breast cancers but the molecular basis for the response of patients is unclear. Here, the authors use samples from an aromatase inhibitor clinical trial and show that tumours from poor responders have more mutations than good responders and also more frequently harbour p53 mutations.
- Pascal Gellert
- , Corrinne V. Segal
- & Peter Donnelly
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Article
| Open AccessStructural basis of checkpoint blockade by monoclonal antibodies in cancer immunotherapy
Immunotherapy is offering patients with cancer new therapy options. Here, the authors report on the crystal structures of some of these therapies bound to their targets.
- Ju Yeon Lee
- , Hyun Tae Lee
- & Yong-Seok Heo
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Article
| Open AccessTargeted inhibition of the COP9 signalosome for treatment of cancer
Dysregulation of protein degradation by the ubiquitin-proteasome system is a feature commonly associated with cancer. Here, the authors develop an orally available small molecule that inhibits CSN5, the proteolytic subunit of the COP9 signalosome, and blocks tumour growth in a xenograft model.
- Anita Schlierf
- , Eva Altmann
- & Bruno Martoglio
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Article
| Open AccessBmi1 marks distinct castration-resistant luminal progenitor cells competent for prostate regeneration and tumour initiation
The polycomb repressor protein Bmi1 has a role in self-renewal and tumorigenesis. Here, the authors use lineage tracing to show that Bmi-expressing cells are a distinct population of cells, primarily found in the luminal compartment, which is castration resistant, can initiate cancer and regenerate prostate.
- Young A. Yoo
- , Meejeon Roh
- & Sarki A. Abdulkadir
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| Open AccessAnti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize
Drugs that sensitize tumour cells to ionizing radiation are prized because they can overcome resistance to radiotherapy. Here, the authors show that anti-tubulin drugs conjugated to cetuximab or trastuzumab can radiosensitize EGFR- or HER2-expressing tumors by increasing DNA damage and cell death due to ionizing radiation.
- Stephen R. Adams
- , Howard C. Yang
- & Sunil J. Advani
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Article
| Open AccessGenetic hierarchy and temporal variegation in the clonal history of acute myeloid leukaemia
Pre-leukaemic clones, together with the propensity to cause disease in mice, are characterized by appearing early in myeloid leukaemia and being found at relapse. Here, the authors identify clones in human samples and find that they are characterized by hierarchically organized genetic lesions, which can be used to track evolution of the disease.
- Pierre Hirsch
- , Yanyan Zhang
- & François Delhommeau
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Article
| Open AccessSynthetic viability by BRCA2 and PARP1/ARTD1 deficiencies
The PARP inhibitor olaparib is an approved treatment method for women with BRCA1 and BRCA2 mutation associated cancers. Here the authors show that olaparib can contribute to synthetic viability of cells if PARP1 is inhibited before BRCA2 loss.
- Xia Ding
- , Arnab Ray Chaudhuri
- & Shyam K. Sharan
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Article
| Open AccessEngineering biosynthesis of the anticancer alkaloid noscapine in yeast
Noscapine is a potential anticancer drug that is traditionally isolated from the opium poppy Papaver somniferum. Here, Li and Smolke reconstitute the noscapine gene cluster in Saccharomyces cerevisiae, to achieve the microbial production of noscapine and related pathway intermediates, and provide new insights into the biosynthesis of noscapine.
- Yanran Li
- & Christina D. Smolke
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Article
| Open AccessHighly variable cancer subpopulations that exhibit enhanced transcriptome variability and metastatic fitness
Phenotypic and genetic intra-tumor heterogeneity have an important role in cancer progression and therapeutic resistance. Here, the authors show that phenotypically variable tumor subpopulations exhibit higher metastatic potential and display enhanced intra-clonal transcriptomic variability, likely promoted by deregulated spliceosome activity.
- Alexander Nguyen
- , Mitsukuni Yoshida
- & Sohail F. Tavazoie
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Article
| Open AccessDifferential clonal evolution in oesophageal cancers in response to neo-adjuvant chemotherapy
Oesophageal adenocarcinoma is often treated with chemotherapy before surgery. Here, the authors sequence cancer samples before and after chemotherapy and examine how the genome changes, focusing on changes in driver gene mutations and differential clonal evolution between good and poor responders.
- John M. Findlay
- , Francesc Castro-Giner
- & Ian Tomlinson
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Article
| Open AccessA miR-192-EGR1-HOXB9 regulatory network controls the angiogenic switch in cancer
The formation of blood vessels in tumours, angiogenesis, is a promising target for therapy. Here, the authors show that microRNA192 has anti-angiogenic functions and negatively regulates EGR1 and HOXB9, and that delivery of this microRNA to tumours in vivocan reduce angiogenesis and tumour growth.
- Sherry Y. Wu
- , Rajesha Rupaimoole
- & Anil K. Sood
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Article
| Open AccessA splicing variant of Merlin promotes metastasis in hepatocellular carcinoma
Merlin plays a crucial role as a tumour suppressor in liver tumorigenesis. Here, the authors show that a splicing variant of Merlin that lacks exons 2,3 and 4 (Δ2–4Merlin) is highly expressed in hepatocarcinoma and promotes tumour metastasis by interfering with the binding of wild-type Merlin to ß-catenin.
- Zai-Li Luo
- , Shu-Qun Cheng
- & Zhong Li
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Article
| Open AccessModel of fibrolamellar hepatocellular carcinomas reveals striking enrichment in cancer stem cells
With no cell lines available, investigating the aetiology of human fibrolamellar hepatocellular carcinomas (hFL-HCCs) has proved problematic. Here, Oikawa et al. establish a model of hFL-HCCs as a transplantable tumour line maintained in immune-compromised mice, which proves rich in cancer stem cells.
- Tsunekazu Oikawa
- , Eliane Wauthier
- & Lola M. Reid
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Article |
PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells
α2δ1 is a marker of liver tumour-initiating cells. Here the authors show that PBX3 is necessary and sufficient for tumour initiation by α2δ1+ cells by regulating transcription of stemness genes, and that PBX3 is targeted by four miRNAs downregulated in α2δ1+ cells.
- Haibo Han
- , Yantao Du
- & Zhiqian Zhang
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Article
| Open AccessEZH2-mediated loss of miR-622 determines CXCR4 activation in hepatocellular carcinoma
Chemokines and their receptors have key roles in tumorigenesis. Here, the authors demonstrate that CXRC4 is overexpressed in hepatocellular carcinoma and is associated with poor prognosis and, mechanistically CXCR4 is increased in expression via EZH2 repression of microRNA-622.
- Haiou Liu
- , Yidong Liu
- & Jiejie Xu
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Article
| Open AccessPARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation
Tumour cells can survive by evading cell death pathways and altering their metabolism to adapt to their local environment. In this study, Iansanteet al. show that the anti-apoptotic protein PARP14 maintains low PKM2 activity, leading to enhanced glycolysis, demonstrating a link between suppression of apoptosis and altered metabolism.
- Valeria Iansante
- , Pui Man Choy
- & Salvatore Papa
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Article
| Open AccessCrucial roles of RSK in cell motility by catalysing serine phosphorylation of EphA2
The EphA2 receptor tyrosine kinase is overexpressed in many cancers and is reported to be phosphorylated by Akt. Here, Zhou et al.show that RSK, rather than Akt, phosphorylates EphA2 on Ser-897, and this regulates cell migration and invasion of metastatic cancer cells.
- Yue Zhou
- , Naoki Yamada
- & Hiroaki Sakurai
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β-Arrestin1 enhances hepatocellular carcinogenesis through inflammation-mediated Akt signalling
Hepatocellular carcinoma can arise from hepatitis as a consequence of persistent inflammation. Here, Yang et al.show that the protein G-protein-coupled receptor adaptor β-arrestin1 promotes hepatocellular carcinogenesis through pro-inflammatory Akt signalling.
- Yidong Yang
- , Yunwei Guo
- & Bin Wu